Noncardiac genetic predisposition in sudden infant death syndrome

Belinda Gray; David J Tester; Leonie Ch Wong; Pritha Chanana; Amie Jaye; Jared M Evans; Alban-Elouen Baruteau; Margaret Evans; Peter Fleming; Iona Jeffrey; Marta Cohen; Jacob Tfelt-Hansen; Michael A Simpson; Michael J Ackerman; Elijah R Behr

doi:10.1038/s41436-018-0131-4

Noncardiac genetic predisposition in sudden infant death syndrome

Belinda Gray, David J Tester, Leonie Ch Wong, Pritha Chanana, Amie Jaye, Jared M Evans, Alban-Elouen Baruteau, Margaret Evans, Peter Fleming, Iona Jeffrey, Marta Cohen, Jacob Tfelt-Hansen, Michael A Simpson, Michael J Ackerman, Elijah R Behr

Department of Cardiology

15 Citations (Scopus)

Abstract

PURPOSE: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls.

METHODS: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis.

RESULTS: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1%] vs. 1/973 [0.1%] p=0.036; SLC6A4, 2/278 [0.7%] vs. 1/973 [0.1%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36%] vs. 4/973 [0.41%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS.

CONCLUSIONS: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible.

Original language	English
Journal	Genetics in medicine : official journal of the American College of Medical Genetics
Volume	21
Issue number	3
Pages (from-to)	641-649
ISSN	1098-3600
DOIs	https://doi.org/10.1038/s41436-018-0131-4
Publication status	Published - Mar 2019

Keywords

Genetics
exome sequencing
molecular autopsy
sudden infant death syndrome
European Continental Ancestry Group/genetics
United States
Humans
Genetic Predisposition to Disease/genetics
Infant
Male
United Kingdom
Genetic Variation/genetics
Case-Control Studies
Gene Frequency/genetics
Whole Exome Sequencing
Exome
Ethnic Groups/genetics
Sudden Infant Death/genetics
Autopsy
Alleles
Female
Mutation
Infant, Newborn

Access to Document

10.1038/s41436-018-0131-4

Cite this

Gray, B., Tester, D. J., Wong, L. C., Chanana, P., Jaye, A., Evans, J. M., Baruteau, A.-E., Evans, M., Fleming, P., Jeffrey, I., Cohen, M., Tfelt-Hansen, J., Simpson, M. A., Ackerman, M. J., & Behr, E. R. (2019). Noncardiac genetic predisposition in sudden infant death syndrome. Genetics in medicine : official journal of the American College of Medical Genetics, 21(3), 641-649. https://doi.org/10.1038/s41436-018-0131-4

Gray, B, Tester, DJ, Wong, LC, Chanana, P, Jaye, A, Evans, JM, Baruteau, A-E, Evans, M, Fleming, P, Jeffrey, I, Cohen, M, Tfelt-Hansen, J, Simpson, MA, Ackerman, MJ & Behr, ER 2019, 'Noncardiac genetic predisposition in sudden infant death syndrome', Genetics in medicine : official journal of the American College of Medical Genetics, vol. 21, no. 3, pp. 641-649. https://doi.org/10.1038/s41436-018-0131-4

@article{f0396ab2e3884d45a12956983e9d9933,

title = "Noncardiac genetic predisposition in sudden infant death syndrome",

abstract = "PURPOSE: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls.METHODS: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62\% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis.RESULTS: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7\%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1\%] vs. 1/973 [0.1\%] p=0.036; SLC6A4, 2/278 [0.7\%] vs. 1/973 [0.1\%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36\%] vs. 4/973 [0.41\%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS.CONCLUSIONS: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible.",

keywords = "Genetics, exome sequencing, molecular autopsy, sudden infant death syndrome, European Continental Ancestry Group/genetics, United States, Humans, Genetic Predisposition to Disease/genetics, Infant, Male, United Kingdom, Genetic Variation/genetics, Case-Control Studies, Gene Frequency/genetics, Whole Exome Sequencing, Exome, Ethnic Groups/genetics, Sudden Infant Death/genetics, Autopsy, Alleles, Female, Mutation, Infant, Newborn",

author = "Belinda Gray and Tester, \{David J\} and Wong, \{Leonie Ch\} and Pritha Chanana and Amie Jaye and Evans, \{Jared M\} and Alban-Elouen Baruteau and Margaret Evans and Peter Fleming and Iona Jeffrey and Marta Cohen and Jacob Tfelt-Hansen and Simpson, \{Michael A\} and Ackerman, \{Michael J\} and Behr, \{Elijah R\}",

year = "2019",

month = mar,

doi = "10.1038/s41436-018-0131-4",

language = "English",

volume = "21",

pages = "641--649",

journal = "Genetics in medicine : official journal of the American College of Medical Genetics",

issn = "1098-3600",

publisher = "Elsevier BV",

number = "3",

}

TY - JOUR

T1 - Noncardiac genetic predisposition in sudden infant death syndrome

AU - Gray, Belinda

AU - Tester, David J

AU - Wong, Leonie Ch

AU - Chanana, Pritha

AU - Jaye, Amie

AU - Evans, Jared M

AU - Baruteau, Alban-Elouen

AU - Evans, Margaret

AU - Fleming, Peter

AU - Jeffrey, Iona

AU - Cohen, Marta

AU - Tfelt-Hansen, Jacob

AU - Simpson, Michael A

AU - Ackerman, Michael J

AU - Behr, Elijah R

PY - 2019/3

Y1 - 2019/3

N2 - PURPOSE: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls.METHODS: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis.RESULTS: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1%] vs. 1/973 [0.1%] p=0.036; SLC6A4, 2/278 [0.7%] vs. 1/973 [0.1%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36%] vs. 4/973 [0.41%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS.CONCLUSIONS: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible.

AB - PURPOSE: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls.METHODS: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis.RESULTS: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1%] vs. 1/973 [0.1%] p=0.036; SLC6A4, 2/278 [0.7%] vs. 1/973 [0.1%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36%] vs. 4/973 [0.41%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS.CONCLUSIONS: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible.

KW - Genetics

KW - exome sequencing

KW - molecular autopsy

KW - sudden infant death syndrome

KW - European Continental Ancestry Group/genetics

KW - United States

KW - Humans

KW - Genetic Predisposition to Disease/genetics

KW - Infant

KW - Male

KW - United Kingdom

KW - Genetic Variation/genetics

KW - Case-Control Studies

KW - Gene Frequency/genetics

KW - Whole Exome Sequencing

KW - Exome

KW - Ethnic Groups/genetics

KW - Sudden Infant Death/genetics

KW - Autopsy

KW - Alleles

KW - Female

KW - Mutation

KW - Infant, Newborn

UR - https://www.scopus.com/pages/publications/85052924773

U2 - 10.1038/s41436-018-0131-4

DO - 10.1038/s41436-018-0131-4

M3 - Journal article

C2 - 30139991

SN - 1098-3600

VL - 21

SP - 641

EP - 649

JO - Genetics in medicine : official journal of the American College of Medical Genetics

JF - Genetics in medicine : official journal of the American College of Medical Genetics

IS - 3

ER -

Noncardiac genetic predisposition in sudden infant death syndrome

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this